| dc.description.abstracteng | Alzheimer’s disease (AD) exhibits substantial clinical and molecular heterogeneity, with
rapidly progressive AD representing a distinct and aggressive subtype. This study provides an
in-depth characterization of stress granules (SGs) and tau oligomers (TauO) in AD subtypes,
uncovering their molecular interplay and contribution to disease progression. Through
biochemical fractionation, immunoprecipitation, and mass spectrometry we identified distinct
SG proteome in slowly progressive AD (spAD) and rpAD, revealing subtype specific
compositional differences. Transmission electron microscopy (TEM) further demonstrated that
rpAD-associated SGs exhibit increased aggregation, altered morphology and greater
association with lysosomal structures, suggesting impaired clearance mechanisms.
Proteomic analysis of SGs in rpAD highlighted differential enrichment of proteins involved in
cytoskeletal organization, ribonucleoprotein assembly and metabolic processes suggesting
dysfunction of related processes. RNA sequencing of SG-associated transcripts highlighted a
widespread depletion of several crucial RNA species linked to neurodegeneration particularly
in rpAD, including those involved in synaptic function, protein translation and RNA
metabolism. Concurrently, TauO characterization revealed that rpAD cases exhibit distinct
phosphorylation pattern through post translational modifications (PTMs) at serine 396 and
serine 422, and enhanced neurotoxicity in neuronal models compared to spAD. Mass
spectrometry-based interactome analysis showed a significant overlap between SG proteome
and potential TauO interactors, supporting a mechanistic link between tau pathology and SG
dysfunction in AD.
Notably, rpAD exhibited a higher number of unique TauO interactors than spAD, underscoring
the presence of subtype-specific molecular signatures. Functional enrichment analysis
identified shared molecular pathways between SGs and TauO emphasizing RNA-binding,
protein quality control and metabolic dysregulation as key drivers of rapid disease progression.
Ultimately, integration of multi-omics datasets revealed that rpAD is characterized by hyper
aggregated state, defective SG clearance, and toxic tau species that likely accelerate disease
progression. This study provides crucial insights into the molecular signatures distinguishing
AD subtypes. | de |